Aop:58

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Status

This is a legacy representation of this AOP. Please see the current version here:

https://aopwiki.org/aops/58


AOP Title

NR1I3 (CAR) suppression leading to hepatic steatosis
Short name: NR1I3 suppression to steatosis

Authors

Michelle Angrish, Brian Chorley

Status

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OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

Under development: Do not distribute or cite.

This AOP page was last modified on 12/11/2016.

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Abstract

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Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Constitutive androstane receptor, NR1l3, Suppression Moderate
PPAR alpha, Inhibition
LXR, Activation
PPARγ, Activation

Key Events

Event Support for Essentiality
SREBF1, Activation Moderate
ChREBP, Activation Moderate
De Novo FA synthesis, Increased Strong
Fatty acid uptake, Increased Strong
Triglyceride formation, Increased Moderate
CD36, Up Regulation Strong
SCD-1, Up Regulation Strong
FAS, Up Regulation Strong
Mitochondrial fatty acid beta-oxidation, Inhibition
Fatty acid, Accumulation
Acetyl-CoA carboxylase-1 (ACC-1), Up Regulation Strong

Adverse Outcome

Adverse Outcome
Liver Steatosis, Increased

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Constitutive androstane receptor, NR1l3, Suppression Directly Leads to LXR, Activation Strong Strong
Constitutive androstane receptor, NR1l3, Suppression Directly Leads to PPARγ, Activation Strong Strong
LXR, Activation Directly Leads to SREBF1, Activation Strong Strong
LXR, Activation Directly Leads to ChREBP, Activation Strong Strong
ChREBP, Activation Directly Leads to De Novo FA synthesis, Increased Strong Strong
Triglyceride formation, Increased Directly Leads to Liver Steatosis, Increased Strong Strong
PPARγ, Activation Directly Leads to SREBF1, Activation Moderate Moderate
PPARγ, Activation Directly Leads to Fatty acid uptake, Increased Moderate Moderate
SREBF1, Activation Directly Leads to SCD-1, Up Regulation Strong Strong
LXR, Activation Directly Leads to CD36, Up Regulation Strong Strong
LXR, Activation Directly Leads to FAS, Up Regulation Strong Strong
LXR, Activation Directly Leads to SCD-1, Up Regulation Strong Strong
FAS, Up Regulation Directly Leads to De Novo FA synthesis, Increased Strong Strong
SCD-1, Up Regulation Directly Leads to Triglyceride formation, Increased Strong Strong
CD36, Up Regulation Directly Leads to Fatty acid uptake, Increased Strong Strong
LXR, Activation Indirectly Leads to PPAR alpha, Inhibition
PPAR alpha, Inhibition Directly Leads to Mitochondrial fatty acid beta-oxidation, Inhibition Strong
De Novo FA synthesis, Increased Directly Leads to Fatty acid, Accumulation Strong
Fatty acid uptake, Increased Directly Leads to Fatty acid, Accumulation Strong
Fatty acid, Accumulation Directly Leads to Triglyceride formation, Increased
Fatty acid, Accumulation Directly Leads to Liver Steatosis, Increased
Mitochondrial fatty acid beta-oxidation, Inhibition Directly Leads to Fatty acid, Accumulation
LXR, Activation Directly Leads to Acetyl-CoA carboxylase-1 (ACC-1), Up Regulation Strong
Acetyl-CoA carboxylase-1 (ACC-1), Up Regulation Indirectly Leads to De Novo FA synthesis, Increased Strong

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Life Stage Applicability

Life Stage Evidence Links

Taxonomic Applicability

Name Scientific Name Evidence Links
human, mouse, rat Moderate

Sex Applicability

Sex Evidence Links

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Weight of Evidence Summary

Summary Table
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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)

References